The complex injectable market is gaining traction in the injectable therapies, however manufacturing of it is critical. In this webinar, lets brainstorm on the downstream criticalities of these molecules and how to handle the same.
ANTIMICROBIAL AGENTS USED AS PRESERVATIVES.pptxDivya Pushp
Preservativeis a substance or chemical that is added to cosmetic product to prevent decomposition by microbial growth or by undesirable chemical changes.
ANTIMICROBIAL AGENTS USED AS PRESERVATIVES.pptxDivya Pushp
Preservativeis a substance or chemical that is added to cosmetic product to prevent decomposition by microbial growth or by undesirable chemical changes.
Content:
Introduction
Ideal Properties
Advantages
Limitations
Types of Microsphere
Method for Preparation
Polymer Used for Preparation
Release of Drug from Microsphere
Application
ABSTRACT
The parenteral administration route is the most effective and common form of delivery for active drug substances with poor bioavailability and the drugs with a narrow therapeutic index. Drug delivery technology that can reduce the total number of injection throughout the drug therapy period will be truly advantageous not only in terms of compliance, but also to improve the quality of the therapy and also may reduce the dosage frequency. Such reduction in frequency of drug dosing is achieved by the use of specific formulation technologies that guarantee the release of the active drug substance in a slow and predictable manner. The development of new injectable drug delivery system has received considerable attention over the past few years. A number of technological advances have been made in the area of parenteral drug delivery leading to the development of sophisticated systems that allow drug targeting and the sustained or controlled release of parenteral medicines.
Sterile filtration of complex injectables by Partha BanerjeeMerck Life Sciences
Sterile filtration and filter validation remain a critical segment during the development of these segments of products. Let's find the same by understanding a checklist and visualize certain case studies.
As the sterile injectable market continues to see rapid growth (~10% to 15% per annum) – outpacing the growth of oral products – it is natural to see the diversity of parenteral product formulations increasing in parallel. The definition of complexity in parenteral formulation development is broad. It varies based on the stage of development and the specific nature of the challenge. A notionally simple, stable reproducible laboratory formulation may carry a level of complexity in aseptic control if routine means of sterilization are unavailable.
Sterile filtration process intensification can bring significant benefits to manufacturers in terms of manufacturing flexibility, reduction of risks, better turn around time, thus achieving significantly higher productivity. We will identify these scenarios with case studies to reduce complications in manufacturing and process development.
Aquasomes are nanoparticulate carrier system but instead of being simple nanoparticles these are three layered self assembled structures, comprised of a solid phase nanocrystalline core coated with oligomeric film to which biochemically active molecules are adsorbed with or without modification.
Sterile filtration of complex injectables by Partha BanerjeeMilliporeSigma
Sterile filtration and filter validation remain a critical segment during the development of these segments of products. Let's find the same by understanding a checklist and visualize certain case studies.
As the sterile injectable market continues to see rapid growth (~10% to 15% per annum) – outpacing the growth of oral products – it is natural to see the diversity of parenteral product formulations increasing in parallel. The definition of complexity in parenteral formulation development is broad. It varies based on the stage of development and the specific nature of the challenge. A notionally simple, stable reproducible laboratory formulation may carry a level of complexity in aseptic control if routine means of sterilization are unavailable.
Sterile filtration process intensification can bring significant benefits to manufacturers in terms of manufacturing flexibility, reduction of risks, better turn around time, thus achieving significantly higher productivity. We will identify these scenarios with case studies to reduce complications in manufacturing and process development.
Sterile filtration of complex injectables by Partha BanerjeeMerck Life Sciences
Sterile filtration and filter validation remain a critical segment during the development of these segments of products. Let's find the same by understanding a checklist and visualize certain case studies.
As the sterile injectable market continues to see rapid growth (~10% to 15% per annum) – outpacing the growth of oral products – it is natural to see the diversity of parenteral product formulations increasing in parallel. The definition of complexity in parenteral formulation development is broad. It varies based on the stage of development and the specific nature of the challenge. A notionally simple, stable reproducible laboratory formulation may carry a level of complexity in aseptic control if routine means of sterilization are unavailable.
Sterile filtration process intensification can bring significant benefits to manufacturers in terms of manufacturing flexibility, reduction of risks, better turn around time, thus achieving significantly higher productivity. We will identify these scenarios with case studies to reduce complications in manufacturing and process development.
Content:
Introduction
Ideal Properties
Advantages
Limitations
Types of Microsphere
Method for Preparation
Polymer Used for Preparation
Release of Drug from Microsphere
Application
ABSTRACT
The parenteral administration route is the most effective and common form of delivery for active drug substances with poor bioavailability and the drugs with a narrow therapeutic index. Drug delivery technology that can reduce the total number of injection throughout the drug therapy period will be truly advantageous not only in terms of compliance, but also to improve the quality of the therapy and also may reduce the dosage frequency. Such reduction in frequency of drug dosing is achieved by the use of specific formulation technologies that guarantee the release of the active drug substance in a slow and predictable manner. The development of new injectable drug delivery system has received considerable attention over the past few years. A number of technological advances have been made in the area of parenteral drug delivery leading to the development of sophisticated systems that allow drug targeting and the sustained or controlled release of parenteral medicines.
Sterile filtration of complex injectables by Partha BanerjeeMerck Life Sciences
Sterile filtration and filter validation remain a critical segment during the development of these segments of products. Let's find the same by understanding a checklist and visualize certain case studies.
As the sterile injectable market continues to see rapid growth (~10% to 15% per annum) – outpacing the growth of oral products – it is natural to see the diversity of parenteral product formulations increasing in parallel. The definition of complexity in parenteral formulation development is broad. It varies based on the stage of development and the specific nature of the challenge. A notionally simple, stable reproducible laboratory formulation may carry a level of complexity in aseptic control if routine means of sterilization are unavailable.
Sterile filtration process intensification can bring significant benefits to manufacturers in terms of manufacturing flexibility, reduction of risks, better turn around time, thus achieving significantly higher productivity. We will identify these scenarios with case studies to reduce complications in manufacturing and process development.
Aquasomes are nanoparticulate carrier system but instead of being simple nanoparticles these are three layered self assembled structures, comprised of a solid phase nanocrystalline core coated with oligomeric film to which biochemically active molecules are adsorbed with or without modification.
Sterile filtration of complex injectables by Partha BanerjeeMilliporeSigma
Sterile filtration and filter validation remain a critical segment during the development of these segments of products. Let's find the same by understanding a checklist and visualize certain case studies.
As the sterile injectable market continues to see rapid growth (~10% to 15% per annum) – outpacing the growth of oral products – it is natural to see the diversity of parenteral product formulations increasing in parallel. The definition of complexity in parenteral formulation development is broad. It varies based on the stage of development and the specific nature of the challenge. A notionally simple, stable reproducible laboratory formulation may carry a level of complexity in aseptic control if routine means of sterilization are unavailable.
Sterile filtration process intensification can bring significant benefits to manufacturers in terms of manufacturing flexibility, reduction of risks, better turn around time, thus achieving significantly higher productivity. We will identify these scenarios with case studies to reduce complications in manufacturing and process development.
Sterile filtration of complex injectables by Partha BanerjeeMerck Life Sciences
Sterile filtration and filter validation remain a critical segment during the development of these segments of products. Let's find the same by understanding a checklist and visualize certain case studies.
As the sterile injectable market continues to see rapid growth (~10% to 15% per annum) – outpacing the growth of oral products – it is natural to see the diversity of parenteral product formulations increasing in parallel. The definition of complexity in parenteral formulation development is broad. It varies based on the stage of development and the specific nature of the challenge. A notionally simple, stable reproducible laboratory formulation may carry a level of complexity in aseptic control if routine means of sterilization are unavailable.
Sterile filtration process intensification can bring significant benefits to manufacturers in terms of manufacturing flexibility, reduction of risks, better turn around time, thus achieving significantly higher productivity. We will identify these scenarios with case studies to reduce complications in manufacturing and process development.
The CMC Journey in the Regulation of Biologicsenarke
Journey in the Development of Biologics Through End of Phase 3
Our Goals
To better understand the FDA’s CMC requirements and expectations for biologic manufacturing and product testing
To better visualize a cost-effective, risk-managed approach to manage these manufacturing processes and products through clinical development into market approval
To better appreciate the challenges involved with controlling safety, potency, and impurity profiles for these products
Journey in the Development of Biologics Through End of Phase 3
Our Goals
To better understand the FDA’s CMC requirements and expectations for biologic manufacturing and product testing
To better visualize a cost-effective, risk-managed approach to manage these manufacturing processes and products through clinical development into market approval
To better appreciate the challenges involved with controlling safety, potency, and impurity profiles for these products
Challenges using Multiple Single-use Systems: Functionality versus Extractabl...MilliporeSigma
As single-use technologies continue to expand in pharmaceutical manufacturing processes, the risk assessment for extractables and leachables becomes increasingly complex. Join this webinar to obtain guidance on how to perform risk evaluation on a process with multiple single-use components.
A Single-Use System (SUS) is typically designed for a specific process step. In many cases, single-use components are chosen based on their functionality. The challenge arises when there are multiple processing steps-- as the different applications and product matrices are evaluated, the complexity of the risk assessment increases. Complexity includes component evaluation, process conditions, and model solvents streams which ultimately relates to the patient safety risk.
This webinar will evaluate the different single-use components with respect to compatibility and extractables and leachables. A case study will be used to demonstrate the complexity and potential concerns when performing a risk evaluation on the manufacturing process.
In this webinar, you will learn:
- Risk assessment of extractables
- Single-use component evaluation
- Complexity when evaluating multiple assemblies
Challenges using Multiple Single-use Systems: Functionality versus Extractabl...Merck Life Sciences
As single-use technologies continue to expand in pharmaceutical manufacturing processes, the risk assessment for extractables and leachables becomes increasingly complex. Join this webinar to obtain guidance on how to perform risk evaluation on a process with multiple single-use components.
A Single-Use System (SUS) is typically designed for a specific process step. In many cases, single-use components are chosen based on their functionality. The challenge arises when there are multiple processing steps-- as the different applications and product matrices are evaluated, the complexity of the risk assessment increases. Complexity includes component evaluation, process conditions, and model solvents streams which ultimately relates to the patient safety risk.
This webinar will evaluate the different single-use components with respect to compatibility and extractables and leachables. A case study will be used to demonstrate the complexity and potential concerns when performing a risk evaluation on the manufacturing process.
In this webinar, you will learn:
- Risk assessment of extractables
- Single-use component evaluation
- Complexity when evaluating multiple assemblies
This presentation gives brief idea about types of inhalation devices, types of DPIs devices, QbD elements, bioequivalence requirement in USA and EU, and marketed DPI products.
The Viscosity Reduction Platform: Viscosity-reducing excipients for improveme...Merck Life Sciences
Protein viscosity is a major challenge in preparing highly concentrated protein formulations suitable for subcutaneous injection. Recently, the Viscosity Reduction Platform (VRP) was introduced and its technical key features and benefits for formulations were discussed. However, highly viscous solutions do not only pose a challenge when administering a drug to a patient, they can also impose technical limitations in the manufacturing process.
This white paper evaluates the effect of the excipients in the Viscosity Reduction Platform on ultrafiltration processes used to produce a highly concentrated formulation of a monoclonal antibody (mAb). Two filtration methods are demonstrated in this work.
Find more information about the Viscosity Reduction Platform on our website: https://www.sigmaaldrich.com/products/pharma-and-biopharma-manufacturing/formulation/viscosity-reduction-platform
Use of Excipients in Downstream Processing to Improve Protein PurificationMerck Life Sciences
Excipients are used to improve the stability of protein-based therapeutics by protecting the protein against a range of stress conditions such as temperature changes, pH changes, or agitation. Similar stresses are applied to proteins during downstream purification. Shifts in pH during Protein A chromatography, subsequent incubations at low pH for virus inactivation, and changes in conductivity in ion exchange chromatography can lead to aggregation, fragmentation, or other chemical modifications of the therapeutic protein. Given the potential impact on the protein’s structural integrity, there is a need for approaches to reduce the risk presented by the conditions during downstream processing. For example, integration of a solution to prevent aggregation of proteins would be a more efficient strategy than implementing steps to remove multimeric forms.
This white paper highlights the results from a recent paper by Stange et. al., in which protein stabilizing excipients such as polyols, sugars, and polyethylene glycol (PEG4000) were used as buffer system additives. Effect of the excipients on elution patterns, stabilization of the monomer antibody, host-cell protein removal, virus inactivation rates and binding capacity of cation exchange chromatography were explored.
Exploring the protein stabilizing capability of surfactants against agitation...Merck Life Sciences
Agitation of therapeutic protein solutions during manufacturing, shipping and handling is one of the major initiators for protein aggregation and particle formation during the life history of a protein drug. Adsorption of protein molecules to liquid-air interfaces leads to the formation of highly concentrated protein surface films. The rupture of these protein films due to various mechanical processes can then result in the appearance of protein aggregates and particles in the bulk solution phase.
One technique to stabilize proteins against stress induced by liquid-air interfaces is the use of non-ionic surfactants. About 91% of antibody formulations commercially available in 2021 contained a surfactant. Polysorbate 20 and 80, composed of a hydrophilic polyoxyethylene sorbitan and hydrophobic fatty acid esters, made up the largest part being employed in 87% of said formulations.
Despite their frequent use in parenteral drug products, concerns have been raised for decades about the application of polysorbates as surfactants in biopharmaceutical formulations. Autoxidation of polysorbate, caused by residual peroxides in polysorbates, can damage the proteins and can further drive the oxidative degradation of polysorbate. Chemical and enzymatic hydrolysis of polysorbate may lead to the formation of free fatty acid particles, which may become visible; and both mechanisms eventually lead to the reduction in polysorbate concentration. Therefore, the purpose of the current study was to compare various molecules for their capabilities to reduced agitation-induced protein aggregation and particle formation; and furthermore, investigate their underlying protein stabilizing mechanisms.
The Viscosity Reduction Platform: Viscosity Reducing Excipients for Protein F...Merck Life Sciences
Protein viscosity is one of the major obstacles in preparing highly concentrated protein formulations suitable for subcutaneous injection.
This whitepaper examines how combining an amino acid with a second viscosity-reducing excipient circumvents adverse effects on protein stability and improves viscosity-reducing capacity.
To find more information about the Viscosity Reduction Platform, please visit our website: https://sigmaaldrich.com/products/pharma-and-biopharma-manufacturing/formulation/viscosity-reduction-platform
Characterization of monoclonal antibodies and Antibody drug conjugates by Sur...Merck Life Sciences
Watch the presentation of this webinar: https://bit.ly/3Pjpjvr
Highlights of this webinar:
- Surface plasmon resonance as a powerful tool for biologic characterization including mAbs and ADCs.
- SPR allows rapid binding analysis in real time without using labels for SARS-CoV-2 receptor binding domain mutations.
- Kinetic data is indicative of possible neutralizing activity allowed assessment of neutralizing ability of therapeutic monoclonal antibodies.
- The application can provide preliminarily efficacy information and facilitated mAbs/ACDs candidate selection process
Detailed description:
Characterization of therapeutic monoclonal antibodies (mAbs) or Antibody drug conjugates (ADCs) is challenging due to their ability to bind to a variety of proteins via their Fc and Fab domains, giving rise to diverse biological functions associated with each domain. The Fc domain of mAbs interacts with Fc receptors with varying affinities, which can influence biological processes such as Complement-dependent cytotoxicity (CDC) and Antibody-dependent cellular cytotoxicity (ADCC), transcytosis, phagocytosis, and/or serum half-life.
An important characteristic of an antibody is its Fc effector function. Antibodies can be engineered to obtain desired binding of the Fc region to Fc receptors expressed on effector cells. Hence, it is crucial to evaluate the binding interaction of mAbs/ADC with Fc receptors in the early phase of drug development to understand the potential biological activity of the product in vivo.
Surface Plasmon Resonance (SPR) is a powerful technique to establish binding kinetics in real-time, label free, and high sensitivity with low sample consumption. Along with target antigen binding, it is crucial to evaluate the binding interaction of antibodies and ADCs with Fc receptors. Our SPR case studies investigated the impact on binding kinetics of ADCs with different linkers and the binding interactions of SARS-CoV-2 spike protein variants and evaluated the neutralizing ability of therapeutic mAbs. SPR characterisation can be facilitated in all stages of the product life cycle to ensure the quality and safety of mAbs and ADCs.
The Role of BioPhorum Extractables Data in the Effective Adoption of Single-U...Merck Life Sciences
Regulatory expectation does require patient safety evaluations with supporting data for manufacturing components that directly come into contact with drug manufacturing process streams. Readily available extractables data can help manufacturers using singleuse technology to accelerate product qualifications, risk assessments and process optimization
This white paper guides you on how to save time and resources with supplier-provided single-use system extractables data and gives you an overview about the overall strategy for Extractables & Leachables. At the end you will find a case study.
Find more information about filters and single-use components on our website: https://www.sigmaaldrich.com/DE/en/services/product-services/emprove-program/emprove-filter-and-single-use-component-portfolio
Watch the recording of this presentation here: https://bit.ly/3zTOpe4
Detailed description:
SARS-CoV-2 showed us that technology supports us during our inspection activity even if on-site visits are not possible. Travel restrictions of various kinds will remain a risk in the future. The use of new technologies has shown that inspections and audits can be carried out despite these restrictions. We will focus on what possibilities the new technologies offer and take a look at the future of inspections and audits.
In this webinar, you will learn:
• Regulatory overview of remote audits
• The technologies needed to support the audit process
• What types of inspections are possible with the use of these technologies
• How audits may look in the future
Presented by:
Daniel Buescher, Product Manager - Digital Solutions
Moving your Gene Therapy from R&D to IND: How to navigate the Regulatory Land...Merck Life Sciences
Watch the recording of this presentation here: https://bit.ly/3SqOsoP
Novel therapies, including cell and gene therapies, continue to be central to innovation in healthcare and represent the fastest growing area of therapeutic medicine. As a consequence, the number of gene therapies undergoing clinical trials has increased significantly in the last five years.
Manufacturing processes for these novel therapeutics are very complex with a high risk of contamination. Regulatory agencies world-wide have responded by issuing guidance to outline their expectations for development and manufacture of cell and gene therapies. Currently, regulatory guidance is not harmonized globally and can often lead to confusion within industry and increased risk of non-compliance.
In this webinar, we'll answer:
• Which regulatory guidelines do you need to comply for your INDs?
• When do you start implementing GMPs and validated assays?
• How do you get your QC testing strategy ‘right the first time’?
• How do you ensure testing is not your rate limiting step for the IND submission?
Presented by:
Manjula Aysola, Senior Regulatory Consultant
Dr. Alison Armstrong, Sr. Director, Technical and Scientific Solutions
Identity testing by NGS as a means of risk mitigation for viral gene therapiesMerck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3RijkHC
Detailed description:
Imagine you’ve just completed a manufacturing run for your viral vector. Identity testing is performed to confirm the vector sequence. But when the results come back the data reveals unexpected sequence variants! With an appropriate risk mitigation testing strategy, this situation can be prevented.
The situation described above is not hypothetical, and happens more that you think, costing valuable time and resources.
Investigatory testing has shown that sequence variants present in starting materials (e.g. plasmids) are likely to make their way to the final product. Adequate identification of low-level variants with an appropriately sensitive method is critical in ensuring the quality of the final product. A risk-based testing strategy, in the context of identity, for viral vector manufacturing will be presented, focusing on key testing points. NGS assays for identity and variant detection will be highlighted due to their extremely sensitive nature compared to traditional approaches.
In this webinar, we'll explore:
• Regulatory requirements for identity testing
• NGS applications for identity testing as compared to traditional methods
• A case study on the impact of not establishing a proper risk-based testing strategy
Presented by: Bradley Hasson, Director of Lab Operations for NGS Services
Latest advancements of melt based 3D printing technologies for oral drug deli...Merck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3A2WcH4
The application of polymer excipients in 3D printing manufacturing is usually limited due to the concerns of filament strength, high processing temperature and large scale manufacturing.
Latest technology developments are targeting a direct melt deposition to simplify the process and enable a constant and efficient process. Two different processing approaches will be presented:
The advanced melt drop deposition, where individual three dimensional geometries can be created by depostition of polymer droplets and the MED® 3D printing technology which allows by precise layer-by-layer deposition to produce objects with well-designed geometric structures.
In this webinar, you will learn:
• Latest advancements of melt based 3D printing approaches
• Application examples for the individual technologies
• Deep dive in the MED® 3D printing technology to design dedicated drug release profiles
Presented by:
Dr. Thomas Kipping, Head of Drug Carriers
Dr. Xianghao Zuo, Deputy Director of R&D, Triastek
CAR-T Manufacturing Innovations that Work - Automating Low Volume Processes a...Merck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3NDNIKe
Automated, fit-for-purpose tools are essential in CAR-T processing to support sustainable manufacturing of clinical and market-approved cell therapy products. This webinar will discuss how the ekko™ Acoustic Cell Processing System uses acoustic technology as a touchless approach to manipulate cells, enabling a modular tool across the CAR-T manufacturing workflow. Typical performance of templated ekko™ System processes for DMSO washout of leukapheresis material, low volume and high cell concentrate for electroporation preparation, and harvest of expanded T cells will be reviewed.
This webinar will also give an early glimpse at the ekko™ Select System for unmatched T cell selection.
In this webinar, you will:
• Uncover how the ekko™ System supports the broad industrialization of cell therapy, with particular focus on how to achieve low volume, high concentrate cell product for critical transduction and transfection steps
• Discover how ekko™ System for wash and concentrate processes throughout the cell therapy workflow achieve high cell recovery, viability, and effective residual removal
• Preview to ekko™ Select, our cell therapy selection platform, to achieve unmatched ease-of-use with direct processing from leukopaks reducing the need for preparation steps
Presented by:
Benjamin Ross-Johnsrud, Acoustic Technology Expert
Robert Scott, Mechanical Engineer III
Viral safety of biologics: What's changing with the ICH Q5A revision?Merck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3t7X9tg
How does the ICH Q5A revision impact viral safety strategies for biologics?
Biologics continue to grow at a fast pace. Manufactured using cell lines of human or animal origin, these are at risk of viral contamination making safety strategies critical. A comprehensive risk mitigation strategy using multiple orthogonal measures is a regulatory expectation. ICH Q5A, the globally-harmonized guideline outlines the expectations. ICH Q5A is currently being revised to address recent scientific advancements including novel therapeutic modalities, new manufacturing paradigms, updates in viral clearance applications, and alternate detection technologies. We’ll discuss the expected changes and potential impact on viral safety strategies with case studies and examples.
In this webinar, you will learn about:
• The Importance of virus testing in biologics products
• Regulatory landscape, expectations for the Q5A revision
• What's new and changing
• Examples of alternate testing schedules, impact on viral clearance
Presented by:
Manjula Aysola, Senior Regulatory Consultant
Alison Armstrong, PhD, Sr. Director, Technical and Scientific Solutions
Improve Operational Efficiency by Over 30% with Product, Process, & Systems A...Merck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3adaxWh
When implementing new automation systems, organizations must consider things like deployment time, user adoption, and costs.
They must also consider the cost of doing nothing – that is, what competitive advantage is lost in standing still? What time and quality is lost in repetitive, manual tasks rather than an automated, digital workflow? What operational efficiencies are lost?
In this webinar we examine how a product, process, and system agnostic automation platform can be deployed faster than traditional system specific software while bringing greater operational efficiencies (in many cases over 30% improvement).
To remain competitive in the market, biopharma manufacturers must adopt automation and digital technologies, but most plants still have island of automation consisting of independently functioning, standalone unit operations. This results in operational inefficiency, regulatory concerns, and a poor understanding of the process and product life cycle.
Taking the first, right step must include considering risks, costs, timelines, and technology alternatives. Traditional automation approaches tied to specific systems, processes, and products are, by their nature, limited; while an agnostic platform will address current biomanufacturing business challenges and ensure future readiness. With the right platform, a phased automation implementation can yield operational efficiency gains of up to 30% and improved product quality and regulatory compliance.
In this webinar, let's explore:
• Challenges of automation and digital technology adoption
• What a product, process, and system agnostic platform entails
• Applications and benefits of a process orchestration platform
• Ensuring future readiness with process orchestration
Presented by:
Braj Nandan Thakur, Global Product Manager - Automation
Insights from a Global Collaboration Accelerating Vaccine Development with an...Merck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3Nbb5ug
Get insights and best practices from a multinational team establishing a platform for vaccine production. See how a long-term collaboration on a bench-scale process used to produce a Virus Like Particle (VLP) vaccine for SARS-CoV-2 was successfully converted to a robust GMP-compatible, scalable process.
The COVID-19 pandemic further emphasized the need for collaboration in the development of urgently needed vaccines and therapeutics. In this webinar, we take you behind the scenes of our collaboration with Technovax and Innovative Biotech in which a scalable VLP vaccine platform was optimized for use in a production facility in Nigeria in response to the need for local production of SARS-CoV-2 vaccines. The flexibility and robustness of the platform will enable its rapid deployment to support the West African pandemic readiness program. Initial development of the VLP process began in late 2019 and by March 2020, was already adapted for production of a SARS-CoV-2 vaccine.
In this webinar, you will learn:
• About building a priceless collaborative network with integrated solutions
• Virus-Like Particle Vaccines
• Process Development Overview and Challenges
• Pre-clinical Results and Next Steps
Presented by:
Jose M. Galarza, PhD,
President and Founder of TechnoVax
Naomi Baer,
Business development consultant, Emerging Biotech, BioProcess division
Youssef Gaabouri, Eng. ,
Associate Director, Head of Sales Middle East & Africa, BioProcess division
Risk-Based Qualification of X-Ray Sterilization for Single-Use SystemsMerck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3vQf0qv
In the single-use bioprocess industry, X-ray irradiation warrants consideration as an alternate sterilization technology. Using a risk-based qualification testing strategy is important when evaluating and implementing equivalent ionizing irradiation sterilization methods.
The urgent need for life-saving therapies as a result of the global pandemic has reinforced the criticality of flexibility in pharmaceutical manufacturing, including sterilization. The single-use bioprocess industry traditionally has employed gamma irradiation sterilization. X-ray irradiation is being considered as an additional sterilization technology for business and supply continuity. We will share a risk-based qualification testing strategy including Extractables and data generated to support comparability of gamma irradiation and X-ray irradiation as equivalent ionizing irradiation sterilization methods.
In this webinar, you will learn about:
• The comparison of gamma and X-ray irradiation sterilization
• A risk-based qualification test strategy
• Data evaluation of gamma versus X-ray sterilized single-use components
Presented by:
Monica Cardona,
Global Senior Program Manager
Paul Killian, Ph.D.,
R&D Director, Analytical Technologies
Rapid replication competent adenovirus (rRCA) detection: Accelerate your lot ...Merck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3MJ4u9V
Testing for presence of replication competent adenovirus (RCA) is a key component to ensure patient safety and a requirement for all biologicals manufactured using adenoviral vectors. For many adenoviral-based products, the RCA assay is a rate-limiting assay for lot release.
Join this webinar to learn about a rapid RCA detection assay currently in development, which combines a 7-day culture assay with a highly sensitive molecular endpoint specific for RCA. The method can detect presence of as little as 1 RCA in adenoviral vector material at an approximate concentration of 5x107 - 2x108 vector particles (VP)/mL, making it a suitable method to meet regulatory requirements while accelerating your lot release timelines.
In this webinar, you will learn about:
• Regulatory framework for adenoviral vector products
• Considerations for lot release testing of adenoviral-based therapies
• Advantages of a rapid method for RCA testing on production lot material
Presented by:
Axel Fun, Ph.D.,
Principal Scientist
Alberto Santana, MBA,
Product Manager, Biologics Biosafety Testing
The High Intensity Sweeteners Neotame and Sucralose: 2 Ways to ace the Patien...Merck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3vQyN7K
Bitter medicines are an important issue, especially for pediatric applications. As several APIs have bitter tasting components, high intensity sweeteners for taste optimization are of great interest. Join our webinar to discover our new sweetener toolbox enabling safe and stable formulations.
Mask bitter aftertaste for a sweeter pill to swallow! Patients’ compliance and the therapeutic benefit are supported by a pleasant taste of pharmaceutical formulations. With the high intensity sweeteners Neotame and Sucralose, you have efficient tools at hand which are superior to other sweeteners in many aspects:
• excellent sugar-like taste profile
• outstanding sweetness factors
• use effectiveness
• enhanced stability
We will present our new toolbox of two high performance sweeteners and focus on aspects of stability, safety, the application in various dosage forms, and market perception.
In this webinar, you will learn:
• How to optimize the patients' taste experience of your pharmaceuticals
• How sweeteners can be differentiated by their sensory profiles and features
• How our new product offering Neotame can be effectively used in your targeted formulations
Presented by:
Almut von der Brelie,
Senior Manager Strategic Marketing
Excipients for Solid Applications
The Developability Classification System (DCS): Enabling an Optimized Approac...Merck Life Sciences
This whitepaper by Dr. Daniel Joseph Price outlines how poorly soluble drug formulations can be designed using the developability classification system (DCS).
The DCS identifies the root cause of low solubility and enables lean, cost-effective and effective formulations to be developed.
#solubility #pharmaceuticalmanufacturing #oralsoliddosage #drugdevelopment
In this webinar, you will learn about:
The advantages of using advanced intermediates to develop ADC therapies
How to increase ADC solubility and efficiency
Fast, small-scale ADC library generation
Seamless supply chain with reduced complexity and regulatory support
The ADCore product line offers versatile intermediates that simplify the synthesis of common ADC payloads (dolastatins, maytansinoids, and PBDs) by greatly reducing the number of synthetic steps. This translates to savings in development and manufacturing costs and shorter timelines to the clinic. To address the poor solubility of many ADC payloads, ChetoSensar™ was developed to significantly increase the hydrophilicity of the drug linker, which has been shown to also substantially increase the efficacy of ADCs and broaden the therapeutic window.
Lastly, the ADC Express™ service leverages conjugation chemistry and analytical expertise to help design and quickly synthesize sets of potential ADC therapies suitable for screening to simplify candidate selection and get ADC therapies to market faster.
Deep Leg Vein Thrombosis (DVT): Meaning, Causes, Symptoms, Treatment, and Mor...The Lifesciences Magazine
Deep Leg Vein Thrombosis occurs when a blood clot forms in one or more of the deep veins in the legs. These clots can impede blood flow, leading to severe complications.
Navigating Challenges: Mental Health, Legislation, and the Prison System in B...Guillermo Rivera
This conference will delve into the intricate intersections between mental health, legal frameworks, and the prison system in Bolivia. It aims to provide a comprehensive overview of the current challenges faced by mental health professionals working within the legislative and correctional landscapes. Topics of discussion will include the prevalence and impact of mental health issues among the incarcerated population, the effectiveness of existing mental health policies and legislation, and potential reforms to enhance the mental health support system within prisons.
One of the most developed cities of India, the city of Chennai is the capital of Tamilnadu and many people from different parts of India come here to earn their bread and butter. Being a metropolitan, the city is filled with towering building and beaches but the sad part as with almost every Indian city
India Clinical Trials Market: Industry Size and Growth Trends [2030] Analyzed...Kumar Satyam
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Growing Prevalence of Lifestyle Diseases
The rising incidence of lifestyle diseases such as diabetes, cardiovascular diseases, and cancer is a major trend driving the clinical trials market in India. These conditions necessitate the development and testing of new treatment methods, creating a robust demand for clinical trials. The increasing burden of these diseases highlights the need for innovative therapies and underscores the importance of India as a key player in global clinical research.
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CHAPTER 1 SEMESTER V - ROLE OF PEADIATRIC NURSE.pdfSachin Sharma
Pediatric nurses play a vital role in the health and well-being of children. Their responsibilities are wide-ranging, and their objectives can be categorized into several key areas:
1. Direct Patient Care:
Objective: Provide comprehensive and compassionate care to infants, children, and adolescents in various healthcare settings (hospitals, clinics, etc.).
This includes tasks like:
Monitoring vital signs and physical condition.
Administering medications and treatments.
Performing procedures as directed by doctors.
Assisting with daily living activities (bathing, feeding).
Providing emotional support and pain management.
2. Health Promotion and Education:
Objective: Promote healthy behaviors and educate children, families, and communities about preventive healthcare.
This includes tasks like:
Administering vaccinations.
Providing education on nutrition, hygiene, and development.
Offering breastfeeding and childbirth support.
Counseling families on safety and injury prevention.
3. Collaboration and Advocacy:
Objective: Collaborate effectively with doctors, social workers, therapists, and other healthcare professionals to ensure coordinated care for children.
Objective: Advocate for the rights and best interests of their patients, especially when children cannot speak for themselves.
This includes tasks like:
Communicating effectively with healthcare teams.
Identifying and addressing potential risks to child welfare.
Educating families about their child's condition and treatment options.
4. Professional Development and Research:
Objective: Stay up-to-date on the latest advancements in pediatric healthcare through continuing education and research.
Objective: Contribute to improving the quality of care for children by participating in research initiatives.
This includes tasks like:
Attending workshops and conferences on pediatric nursing.
Participating in clinical trials related to child health.
Implementing evidence-based practices into their daily routines.
By fulfilling these objectives, pediatric nurses play a crucial role in ensuring the optimal health and well-being of children throughout all stages of their development.
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The speakers included:
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Dr Hans Groth, Chairman of the Board, World Demographic & Ageing Forum
Professor Ilona Kickbusch, Founder and Chair, Global Health Centre, Geneva Graduate Institute and co-chair, World Health Summit Council
Dr Natasha Azzopardi Muscat, Director, Country Health Policies and Systems Division, World Health Organisation EURO
Dr Marta Lomazzi, Executive Manager, World Federation of Public Health Associations
Dr Shyam Bishen, Head, Centre for Health and Healthcare and Member of the Executive Committee, World Economic Forum
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Addressing Downstream Challenges with Complex Injectables
1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Sterile filtration
of complex
injectables
Partha Banerjee
Senior Technology Consultant
2. The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada
2
3. Agenda
1
2
3
Background
Considerations for Sterile
filtration of liposomes
Liposome sterilization
methodology
4
5
Regulatory Guidelines
Essential parameters-
our observations
6
Sterile filtration of viscous
formulations
3
7
Sterile filtration of oils,
emulsions and ointments
5. • As per the US Food and Drug Administration (FDA), complex parenteral
products are those formulations which contain either complex ingredients or
API, complex formulation, i.e., delivery carrier, complex route of
administration, complex dosage form, or complex drug device combination
.
• The manufacturing of the complex injectable products is different and a great
level of observation of quality and care is required during their manufacturing,
packaging, distribution, and storage.
• Complex injectables have gained increasing attention due to their widespread
use in life-threatening and chronic diseases treatments. The category includes
diabetes, oncology, and hormonal therapy to name but a few.
Complex injectables – Background
Sterile Filtration of Complex Injectables
5
6. Complex injectables – what are they?
Complex drug products have become so prevalent that the FDA has defined them with the following
categories:
• Products with complex active ingredients (e.g., peptides, polymeric compounds, complex mixtures of
[active pharmaceutical ingredients]); complex formulations (e.g., liposomes, colloids); complex routes
of delivery (e.g., locally acting drugs, complex ophthalmological products and otic dosage forms that
are formulated as suspensions, emulsions, or gels); or complex dosage forms (e.g., implantables,
transdermals, metered dose inhalers, extended-release injectables
• Complex drug-device combination products (e.g., auto-injectors)
• Other products where complexity or uncertainty concerning the approval pathway or possible
alternative approach would benefit from early scientific engagement.
Complex processing challenges include, among others, aseptic manufacturing, the inclusion of highly
potent compounds, milling/particle engineering, spray drying, extrusion, and microfluidization.
Ref: ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin, Guidance for
Industry, FDA, May 2021.
7. Solubilization &
Bioavailability
Enhancement
Techniques
Drug-Eluting
Systems
The Four Categories of Complex Drug Products
In considering the above, complex drug products encompass a wide range of technologies and dosage
forms. However, we’ve found that these complex products generally revolve around four conversations
or categories:
Sterile complex
injectables
Highly Potent
APIs and/or
Controlled
Substances
Sterile Filtration of Complex Injectables
7
8. • The FDA requires certain types of drug products to be
provided as a sterile dosage forms to avoid the possibility of
microbial degradation or infection occurring because of their
use.
• This includes several types of drug products,
including injectables (small or large volume parenteral
products), ophthalmic drugs, otic dosage forms,
and implantable products.
Sterility of finished dosage forms can be assured via different
processes
Terminal Sterilization
Aseptic Manufacturing
Sterile Filtration
Sterile Complex Injectables
Sterile Filtration of Complex Injectables
8
9. • Filtration is used for clarification purpose
(clarification filtration) and/or to sterilize solution
using sterilizing grade filter membranes (0.2 µ or
smaller pore size filters).
• Filtration of parenteral products ensures removal
of particulate matter and can be used either for
clarification or for sterilization purposes.
• As it’s a critical operation we classify filtration as
per
• Criticality and point of use.
• Usage.
Sterile filtration – Notable points
Sterile Filtration of Complex Injectables
9
10. Filter in final fill – top 3 segmentations -
Utility filters
Where process fluids come from
facility-wide systems, are not
tailored to a specific process and
do not have contact with the
drug substance or potential drug
substance.
Part of a No-Impact System -
Where the equipment of system
has no impact, direct or indirect,
on product quality (ISPE
Commissioning & Qualification
Baseline Guide (2001))
Filter does not affect product
quality (e.g. distribution gas
filter, water prefilter)
Critical
• Where process fluids “are in
direct contact with sterile final
product or critical surfaces of
the associated equipment.”
(PDA TR26)
• Part of Direct Impact System -
equipment or system that will
have focused and immediate
impact on product quality
(ISPE Commissioning &
Qualification Baseline Guide
(2001))
• Filter directly affects
product quality (e.g. sterile
hold vessel vent filter, sterile
liquid filter)
Moderately Critical
• Where process fluids “will
not be in direct contact with
exposed sterile product or
surfaces.” (PDA TR40)
• Part of an Indirect Impact
System - equipment or
system expected to have
incidental or secondary
impact on product quality
(ISPE Commissioning &
Qualification Baseline Guide
(2001))
• Filter indirectly affects
product quality (e.g. vent
filter in grade D, bioburden
reduction filter)
Sterile Filtration of Complex Injectables
10
11. Filtration Portfolio – classified as per usage
Particulate Control Sterility Assurance
(LRV: 107 CFU/cm2)
Bioburden Control
(LRV: 106 CFU/cm2)
Milligard®
PolysepTM II
LifegardTM
Durapore®
(0.22 um)
Millipore
Express®
SHR
Millipore
Express®
SHF
Durapore®
(0.45 um)
Milligard®
PES
(0.2 um)
Milligard®
PES
(0.45)
Milligard ®
PES
(0.8 um)
Millipore
Express®
PHF
Sterile Filtration of Complex Injectables
11
12. In this presentation we will be discussion the
sterile filtration and filter validation approach of
Liposomes, nano emulsions and viscous fluids.
14. Liposomes Characterization
Size: small, intermediate, or large
Number of lipid bilayers,
composition, and mechanism of
drug delivery
Small unilamellar vesicles (SUV)
− comprise a single lipid bilayer.
Diameter ~25 to 75 nm.
Large unilamellar vesicles (LUV)
− comprise of a single lipid bilayer.
Diameter >75 nm.
Multilamellar vesicles (MLVs)
comprise
− Contain many concentric lipid
bilayers. Diameter ~ 1-5 μm.
14
15. Preparation Methods for Liposomes
Three common approaches
Preparation of globules Size reduction Purification
The liposome preparation method affects purification!
15
16. PDI – Poly dispersity index
PDI is basically a representation of distribution of size populations within a given sample
Degree of non uniformity of size distribution particles
Indicates a monodisperse system.
PDI is a very essential parameter and its analysis helps to understand the size distribution of globule
based formulations.
17. Z Average Value
• The z-average is an intensity-based overall average size based on a specific fit to the raw correlation
function data. Basically the particle size.
Zeta Potential
• The zeta potential of a particle is the overall charge that the particle acquires in a particular medium.
Knowledge of the zeta potential of a liposome preparation can help to predict the fate of the liposomes
in vivo.
• Measurement of the zeta potential of samples is done using the technique of laser Doppler velocimetry
17
19. Liposome Sterilization Methods: Advantages vs disadvantages
Ref: Liposomes as sterile preparations and limitations of sterilisation techniques in liposomal manufacturing ;April 2013;
Asian Journal of Pharmaceutical Sciences 8(2):88-95
19
20. Liposome Sterilization
Heat sterilization
• Not generally accepted
o Lipid/active not heat stable
o Leakage
o Safety issues
Gamma Irradiation
• Not generally used
• Degradation of lipid and
cholesterol
• Safety issues not assessed
• Cryo-radiation also not
effective
Sterile filtration
20
21. Liposome Sterilization by Filtration – the riddle
Widely used
Limited by vesicle size and size distribution
Very little published information
Challenges:
− allow particles (vesicles) of up to 300 nm to pass through
− retain bacteria that can be as small as 200 nm (width)
Lipid Globule B. Diminuta
21
23. Section 3 – Discussion on Liposome drug products – Guidance for Industry
Description of Manufacturing Process and Process Controls
We recommend including a detailed process flow diagram and a description of unit operations
with ranges for the process parameters and process controls.
These ranges should be supported by pharmaceutical development studies. The process and
mechanism of liposomal drug loading, as well as the removal of free (un-incorporated) drug
from the liposome formulation via purification should be described in detail. The
manufacturing process should be validated to demonstrate manufacturing process
consistency and reproducibility before commercial distribution.
Liposome drug products are sensitive to changes in the manufacturing conditions, including
changes in scale (size of the batches). Appropriate process controls should be established
during product development.
Prior knowledge can be leveraged and risk assessment techniques can be used to identify
manufacturing process parameters that potentially affect finished product quality.
Some examples of manufacturing process parameters that may affect liposome drug
performance are shear force, pressure, pH, temperature, batch-size-related hold times,
lyophilization parameters, etc. You should provide adequate justification for the selection of
the operating ranges for different batch sizes.
The physical and chemical complexity of liposome drug products present unique challenges to
the sterilizing filtration process. For example, components of liposomes could interact with the
filter matrix and clog it. Therefore, validated product-specific purification and sterilization
methods should demonstrate the ability of the microbial sterilizing filters to function correctly,
without compromising the integrity and structure of liposomes.
23
Ref: Liposome Drug Products, Guidance for Industry, FDA, April 2018
24. Regulatory Comments - Sterilizing Filtration of Liposomes
“Bulk holding times have been minimized or eliminated to control potential microbial
contamination. In response to a concern raised with respect to microbial contamination, a
pre-sterilized bioburden limit was adopted by the applicant above which batches will be
rejected.”
EMEA Scientific Discussion Documents
http://www.emea.eu.int
“The particle size distribution is measured as an important part of the in-process
controls.”
“…..followed by two 0.22 micron sterile filtration steps, aseptic filling, and
lyophilisation.”
25. Or – Can we follow draft guidance?
25
Ref: US Department of Health and Human Services, Food and Drug Administration, CDER: April 2018
26. We accept the potential challenges….Sterile filtration
• The sterility of such liposome solutions is typically ensured using
0.2μm rated sterilizing grade membranes, but due to the high
viscosity and low surface tension of these formulations, they can
cause pre-mature blocking and increased risk of bacterial
penetration through a 0.2μm sterilizing grade membrane.
• The low surface tension of liposome solutions affects the contact
angle with membrane and reduces bubble point leading to
bacterial penetration through the membrane.
• This poses a great challenge to select an appropriate
sterilizing grade membrane for a given process and for filter
manufacturers to develop a sterilizing grade membrane that
specifically addresses these needs.
27. Can I consider Aseptic Manufacturing?
Raw materials (including
organic and aqueous solvents,
the natural sources of lipid
components as well as other
additives such as buffers) are
sterilised after passing 200
nm filters.
The equipment can
be autoclaved and
sterilised.
Liposomes are
prepared and then
assembled into their
containers via
aseptic filling
Sources of contamination :
environmental air, operating personnel and the water for drainage) should be critically controlled by performing the filling process on work stations
in clean rooms.
Risk of contamination during aseptic processing remains
Especially if the initial raw materials are not sterilised adequately.
Limitations with natural sources of lipid components
Can only be subjected to filtration due to possible physicochemical degradation.
Contaminants
In the raw materials or introduced during manufacturing cannot be removed from the final product during aseptic
manufacturing is performed.
Terminal sterilization - active process of removing
Aseptic filling, and aseptic manufacturing - passive process of avoiding contamination
31. Considering Particle size – Effect of Operating Parameters
31
Increased stirring rate -
• could improve droplet dispersion
• prevent droplet coalescence
• results in smaller apparent particle size
Optimum dispersion conditions -
• The dispersion condition of the droplets
changes according to its concentration in
the poor solvent.
• Therefore, the effects of feed rate of good
solvent and poor solvent ratio is important
• It controls the droplets concentration in
poor solvent, on the particle size of
nanospheres.
31
32. Considering elevated temperature of feed-
• At elevated temperature lipid membrane
passes from tightly ordered gel state (stable)
to a liquid crystal phase (metastable or
unstable)
• Freedom of movement of the individual
molecule is higher.
• This is due to the fatty acid chain adopting a
new conformation other than the all trans
state chain configuration, such as a gauche
confirmation state (chain tilt phenomena)
33. Considering sterile filtration - Case Study 1
Goals:
• Prefilter selection
• Understand the effect of high temp. and
pressure on the feed.
• Note – Particle size was below 150
micron but showed poor flow in SGF
Observations:
• Depth media works well compared to
membrane filters.
• High pressure may facilitate filtration,
but equally there is a risk of bleeding
and coagulation of particles.
• If particles coagulate, even taking the
feed temperature to phase transition
may not show any advantage in flow rate
through sterilizing grade filters.
34. Considering sterile filtration - Case Study 2
FEED
Goals:
Sterile filtration operation.
• The PDI was 0.32, particle size was 84.3
nm, D90 was 1310 nm.
• Pressure applied was 15 PSI, feed
temperature equivalent to 60 degree C.
Observations:
• Its not always mean particle size, In the
sample analysis provided (Malvern particle
size analyser) the D90 value is 1310 (1.3
micron), this depicts that 90% of particles
are lesser than 1.3 micron and 10% more
than 1.3 micron.
• Similarly, the D90 value of the finished
product is 203 nm (0.203 micron) hence
both the solutions are difficult to filter by
0.2 um filter
• It is suggested that the particle size distribution should be
controlled in the liposome manufacturing stage.
• According to our experiences 150-200 nm samples can be
tried and closer the D90 value is to 200 nm lesser and lesser
is the throughput.
34
35. Goal:
sterile filtration.
The PDI was 0.15, particle size
was 90 nm, D90 was 160 nm.
Pressure applied was 15 PSI,
feed temperature RT!!
Observations:
Depth media works well
compared to track itched
membrane.
According to our experiences
150-200 nm samples can be
tried.
The final filtration area was
significantly less and could be
replicated.
Considering sterile filtration - Case Study 3
37. Sterile Filtration of Oils, Emulsions and ointments.
• Most pharmaceutical fluids are water based. But several hydrophobic APIs (Active Pharmaceutical
Ingredients) are often dissolved in an oily base, such as vitamins etc.
• Many of these components are heat sensitive and therefore sterile filtration is the most preferred way.
Examples of oily substances which are filtered are soy bean oil, castor oil, sesame oil, paraffin (liquid
and solid at ambient temperature), silicon oils etc.
• Examples for Emulsions used in the pharmaceutical industry are adjuvant solutions for vaccines or
Liposomes which are capable to solubilise hydrophobic APIs in a water environment. Other examples
include narcotics which is administered in soy bean oil in water emulsion with egg lecithin. Many
emulsions are non-Newtonian therefore flow over pressure curve is not linear.
• Some ointments can be heated up to more than 100°C but there are chances that the bacteria spores
can even survive. For that reason the preparation of oily pharmaceuticals got in the focus of the
regulatory bodies. By sterile filtration bacteria spores can be eliminated reliably.
37
38. High flow rates
Drying of the
filtration
equipment
Top points to consider while handling these formulation -
Product
specific
integrity
testing
Filter validation
aspects -
Sterile Filtration of Complex Injectables
38
39. Optimizing the filtration train –
• Flow rate estimation prior to a filterability trial roughly can help. For this Darcy's Law utilised. Provided
we are working with a non Newtonian liquid. Very essential when we develop the formulation.
• This equation describes the flow of a fluid through a porous medium: Where Q is the flux or discharge
per unit area, e.g., m /s. Permeability of the medium, k (Sqm ) cross sectional area A (Sqm), and the
pressure drop (delta P), all divided by the dynamic viscosity, μ and the length the pressure drop is
taking place over.
• There are certain requirements for the sterilizing grade filtration of oils. Express range of filters are the
most suitable for filtration of oil containing liquids. So Polyethersulfone and Polyamide have good
chemical compatibility. Optimizing robust prefilters like Milligard PES (of varied pore sizes) can really
aid up the over process economics.
• Other important considerations include single use application in the process.
40. Filter validation aspects -
• Considering Validation aspects for sterile filtration
applications a bacteria challenge test. (BCT) has to
be performed. Prior to this test in a Viability study it
has to be demonstrated.
• Due to the high viscosity at ambient temperature of
different oily substances the filtration is performed at
60 to 80°C. At this temperature there is no viability
of the test bacteria given and we may need to
perform a two stage study.
• Unclear composition of different oils avoids a direct
detection in the contact solution specifically during
extraction and analysis.
• After filtration the oily liquid can not be removed by
water flushing from the membrane. For integrity
testing Product specific Integrity Test values can be
established for direct IT measurement after filtration.
42. Sterile Filtration of Viscous formulations -
• Viscosity enhancers are key ingredients in many lens care solutions and ophthalmic prescriptive drug
products.
• These additives are commonly cellulose based compounds but hyaluronic acid is becoming increasingly
popular in new formulations.
• Solutions containing viscosity enhancers can present difficulties during sterile filtration due to batch to
batch variability.
• Even with careful optimisation of the mixing process, premature filter blockage is still common
resulting in frequent filter changeouts mid-batch, product loss and increased processing time.
• And they pose challenges for sterile filtration.
43. • Multiple filter changeouts during batch processing: Premature filter clogging is evident even after
careful optimization of manufacturing process (eg Mixing) and filtration train.
• Product loss –
• The influence of raw materials and process parameters – Which may include granularity of these
cellulose based viscosity enhancers, Mixing techniques.
• Batch to batch variation.
• The temperature of the solution is also a very important factor during the filtration process, increasing
the temperature can promote gelation of the solution that will lead to premature clogging of a filter.
• What about binding of preservatives or essential API of the formulation to filter matrix – when flow rate
is less, contact time is on the higher sides.
• The filterability of solutions can change significantly depending on the time between mixing and
filtration.
• Sterile Filter validation.
Top points to consider while handling these formulation -
44. Optimizing the filtration train -
• Volume maximization study followed by a recheck during pilot scale runs –
• Advantages of composite asymmetric filter geometry
• Usage of a proper safety factor
To allow for process variability due to feed, process and membrane device in a robust process, a safety factor is typically included to define a
required filtration surface area. The required area for a process will be the minimum surface area for an average performance times the
safety factor. The actual variability of a process needs to be defined on a case-by-case basis. In absence of a detailed characterization study,
one could use the following typical economically rationalized safety factors for various unit operations as described in Herb Lutz, Journal of
Membrane Science 341 (2009) p268–278. Exact safety factors can be defined through experimentation. In case of anticipated large
variations (high relative standard deviation. RSD), safety factors more than recommended safety factor can be included in defining the
required surface area. In case specific information is available around low anticipated variability, a smaller safety factor can be used.
44
46. Approach 1 – Imitate process -
Complex
Injectables
47. Approach 2 – Pre-screening study (Filter validation)
Conducting the pre-validation screening study is not mandatory. But, if there is passage, it might be
easier to determine the mitigation plan prior to the retention validation instead of a retention test failure
investigation.
Assess – Process
duration, Actual
temperature, Actual
pressure, Actual
scale down volume
Important consideration –
Stable parameters.
Calculate – Scale down
volume, achieved per Square
surface area of the filter
Important consideration –
Process contact time
Pre–screening to be conducted with
one filtration line only.
Important consideration –
Pressure based study and no
recirculation mode.
Inoculation
47
49. Approach 4 – Selecting a well defined prefilter –
Like Milligard® PES
Benefits:
Fast flow and high throughput
Validated bioburden reduction (1.2/0.2 μm nominal and 1.2/0.45 μm pore sizes only)
Predictable scalability from small to production scale devices
High thermal stability: compatible with steam-in place and autoclave sterilization methods
Caustic stable
Gamma stable and available in single use assemblies
50. Points to consider in terms of
Filterability
Filter validation.
Sterile Filtration of Complex Injectables
50
51. Filterability
Process considerations:
Keep vesicle size and size distribution small
Incorporate active in bilayer when feasible
Select process temperature in relation to Tc and lipid composition
Pre-wet filters with vehicle/buffer
Increase differential pressure gradually
May need to exceed certain differential pressure to initiate flow
Filter considerations:
Evaluate filterability early in process development
Evaluate different filter media types, hydrophilic PES generally works the best
Use pre-filtration to optimize filterability
51
52. Filter validation - Bacterial Retention study
Evaluate sterilization approach early in process development
Choose synthetic lipids when possible
Keep vesicle size and size distribution small
Evaluate different media pore size ratings and types
Consider “new technology” – Like stacked disc formats (Millipak® range of filters
with Durapore® membrane, high area device, AMPP (aseptic multi-purpose port)
Hydrophilic PES generally works the best
53. And we stand unique -
M LabTM /
Validation lab.
support
Liquid filters -
Durapore®
Liquid filters –
Millipore
Express ®
Gas filtration -
Aervent®
Next Gen
technology
Documentation
• Trusted name brand >40 yrs.
• Extreme strength
• Durable for reuse
• Low protein - preservative
binding
• High thermal and gamma
stability
• Fast flow
• Broad chemical compatibility
• Excellent wettability after
autoclaving
• High thermal and gamma stability
• From-buffer/media/protein
intermediates to viscous/complex
molecules – wide application.
• Meant for critical applications
• Sterility assurance
• Liquid bacterial retention
• Virus aerosol retention testing
• High air or gas flow rate
• Oxidation resistance for a long
service life
• Greater hydrophobicity
• Stacked disc membranes – for
higher flow/low hold up.
• AMPP – Aseptic multipurpose port –
protects product from
contamination, maintains sterility
• High area device - Unique shape,
taller pleats and narrower core –
double membrane area.
• Composite asymmetric membranes
– no its not 2 separate layers.
Facilitating qualification
processes
Supporting risk assessment,
management and mitigation
Expediting approval
preparation and extending
compliance
• Want a pilot scale demo run.
• What IT troubleshooting – real
time view
• Visualize scale up scenario.
• Project status.
• Sample recon – if difficult to ship
• Ready to audit labs.
54. Product Support Services - Uniqueness continues -
Process Reviews
Filter review
Compliance review
Integrity testing
review
Steam in Place review Training
• Filtration
• Integrity testing -Introductory
& Advanced Troubleshooting.
• IT testing - Compliance
• Filter validation
• SIP & Sterilization
• Microbiological analysis
• Sterility Testing
Sterile Filtration of Complex Injectables
54